BISQUINOLINES .1. N,N-BIS(7-CHLOROQUINOLIN-4-YL)ALKANEDIAMINES WITH POTENTIAL AGAINST CHLOROQUINE-RESISTANT MALARIA
BISQUINOLINES .1. N,N-BIS(7-CHLOROQUINOLIN-4-YL)ALKANEDIAMINES WITH POTENTIAL AGAINST CHLOROQUINE-RESISTANT MALARIA
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DOI：
10.1021/jm00089a025
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发表时间：
1992-05-29
影响因子：
7.3
通讯作者：
MILHOUS, WK
中科院分区：
文献类型：
--
作者：
VENNERSTROM, JL;ELLIS, WY;MILHOUS, WK
根据哌喹等几种双喹啉类化合物对耐氯喹疟疾具有显着活性的观察结果，合成并筛选了 13 种 N,N-双-(7-氯喹啉-4-基)烷二胺，并筛选了体外抗恶性疟原虫和体内伯氏疟原虫。 13 种双喹啉中，有 12 种的耐药指数显着低于氯喹；阻力指数显然与体外或体内活性无关。除两种化合物外，体外和体内活性之间存在合理的相关性。 13 种双喹啉中的 7 种对氯喹敏感 (D-6) 和抗性 (W-2) 恶性疟原虫克隆的 IC50 均小于 6 nM，并且在 640 mg/kg 的剂量下对伯氏疟原虫有疗效。与氯喹相比，这些双喹啉在治疗剂量水平下没有表现出任何毒性死亡。然而，四种双喹啉会引起注射部位的皮肤损伤。在具有两个碳原子连接桥的双喹啉中观察到最大活性，其中降低的构象迁移率似乎增加了活性。双喹啉 3 ((+/-)-反式-N1,N2-双(7-氯喹啉-4-基)环己烷-1,2-二胺不仅是体外最有效的双喹啉，而且其体内活性也明显独特——在 160 和 320 mg/kg 的剂量下分别达到 80% 和 100% 的治愈率。 总之，这些初步结果支持了双喹啉可能有用的前提对抗耐氯喹疟疾的药物。
On the basis of observations that several bisquinolines such as piperaquine possess notable activity against chloroquine-resistant malaria, 13 N,N-bis-(7-chloroquinolin-4-yl)alkanediamines were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Twelve of the thirteen bisquinolines had a significantly lower resistance index than did chloroquine; the resistance index was apparently unrelated to either in vitro or in vivo activity. Except for two compounds, there was a reasonable correlation between in vitro and in vivo activities. Seven of the thirteen bisquinolines had IC50's of less than 6 nM against both chloroquine-sensitive (D-6) and -resistant (W-2) clones of P. falciparum and were curative against P. berghei at doses of 640 mg/kg. In contrast to chloroquine, these bisquinolines did not show any toxic deaths at curative dose levels. Four bisquinolines, however, caused skin lesions at the site of injection. Maximum activity was seen in bisquinolines with a connecting bridge of two carbon atoms where decreased conformational mobility seemed to increase activity. Bisquinoline 3 ((+/-)-trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine was not only the most potent bisquinoline in vitro, but was clearly unique in its in vivo activity-80% and 100% cure rates were achieved at doses of 160 and 320 mg/kg, respectively. In summary, these preliminary results support the premise that bisquinolines may be useful agents against chloroquine-resistant malaria.